We have identified a novel hereditary demyelinating disorder in children and demonstrated highly specific magnetic resonance spectroscopic alterations that appear unique to this disorder. The latter observation has allowed us to identify a cohort of patients who are undergoing detailed biochemical and molecular biologic investigation. These studies will serve to advance understanding of the hereditary leukodystrophies of unknown etiology. The latter illnesses are not infrequent in occurrence and are particularly devastating for children. We have initiated a series of investigations to define sensitive disease progression markers in patients with Fabry's disease. Patients with this disorder frequently suffer severe neuritic pain early in life and ultimately succumb to cardiac, renal or cerebrovascular disease in the fourth or fifth decade. We have discovered novel MR imaging findings in the CNS of these patients that appear to develop predictably between 35 and 40 years of age. In addition, we have observed previously unreported physiological abnormalities of small myelinated and unmyelinated fibers in the peripheral nervous system. By performing quantitative analyses of the number of free nerve endings in the skin, we have discovered a marked thinning of terminal dendritic arborizations as the disease progresses. Immunohistochemical analyses demonstrate significant regenerative activity in these nerve endings. Further development of these methodologies will permit us to use these parameters to evaluate the effects of enzyme replacement therapy and gene replacement therapy in patients with Fabry's disease.